The research proposed here expands our effort to establish methods for the selective control of painful sensations using local anesthetics. We plan to elaborate from our present emphasis on axonal phenomena in vitro to record from the peripheral and central projections of neurons in vivo whose physiological role will be identified by unit recording during a spectrum of natural stimuli and motor activities. We will then characterize the actions of anesthetics on these functionally classified nerve fibers using methods developed in our present work. Effects on the CNS of peripheral nerve blocks will be studied by comparing unit responses from the dorsal horn of the spinal cord, and from several mode-selective ascending pathways. The neurophysiological consequences of epidural and intrathecal application of local anesthetics also will be investigated by measuring the relationship between impulses incoming via peripheral nerves, and the responses of spinal units, ventral roots, and centrally projecting pathways. To restrict the diffusion of anesthetic molecules within the spinal cord and epidural space, they will be leashed to macromolecules or synthesized into biologically active polymers. Quaternary amine derivatives of local anesthetics, which inhibit synaptic transmission while sparing axonal conduction, will also be injected intrathecally to help define alternative mechanisms for spinal anesthesia. Recording sites and radioactively-tagged free anesthetics, as well as those leashed to macromolecules or present as polymers, will be localized using light microscopy and radio-autography. To further specify the mechanism of action of anesthetics on spinal neurons we will study such cells in tissue culture by standard intracellular and path-clamp methods, examining the effects of anesthetics and derivatives on single-channel events activated by neuro-transmitters and on transmission between synaptically coupled cells. Studies on isolated peripheral nerve will be extended or physiologically characterized single units further refining the role of changes in pH, pCO2 and temperature on local anesthetic block of functionally characterized fibers.